Seasonal growth and shrinkage of brain regions involved in control of birdsong provides a striking and unique opportunity to investigate the mechanisms regulating neuronal turnover associated with natural variation in steroids, and the functional consequences of this neural plasticity for sensorimotor learning. The aims in this proposal address fundamental issues of neural plasticity, and neuronal turnover in particular, in adult brains. These include the role of steroid hormones and neurotrophins in neuronal birth and death (Aims 1-2), the role of neurotrophins in neuronal activity that influences neurogenesis (Aim 3), and the coordinated expression of families of genes important in regulating functionally related processes of neurogenesis, neuronal protection, death, and activity (Aim 4). The birdsong system excels as a model for studies of neural plasticity; it is a well-defined and tractable neural circuit that shows extreme seasonal plasticity and regulates song, a learned sensorimotor behavior that is easily analyzed. This research will advance the field by 1) elucidating the mechanisms underlying the functional linkage between neuronal birth and death in adult brains (Aims 1,2); 2) providing the first evidence that neurotrophins influence the electrophysiology of neurons in the song system (Aim 3); 3) moving this field beyond the level of single gene analysis by opening up analysis of microRNA expression as a molecular mechanism for coordinating the expression of gene families that regulate the component cellular processes of adult neuroplasticity (Aim 4). PUBLIC HEALTH RELEVANCE: Steroid hormones have potential for use as neuroprotective agents in the treatment of stroke and a variety of neurodegenerative and mental health disorders. They are also of increasing concern as drugs of abuse. This work will examine the fundamental mechanisms by which these potent hormones influence neuronal birth, death, and gene expression.